Dendritic cells (DCs) compose a group of antigen presenting cells together with B cells and macrophages. Among various antigen presenting cells, DCs are known to have the highest antigen-presenting capacity. DCs stimulate and sensitize the peripheral immune system, which is centered on the acquired immunity mediated by T cells, B cells, NK/NKT cells, and the like, and hence, DCs are thought to function as a director or control tower of the immune system. One of the central roles of DCs is to induce the acquired immune system by incorporating foreign matter from outside the body, antigen proteins in the body, and the like, degrading them, and then presenting them as antigens. With another function of DCs, DCs respond to inflammatory stimuli, so as to produce various inflammatory cytokines.
Various immune diseases (e.g., allergies, autoimmune diseases, and enteritis) are currently increasing explosively around the world. As a cause of such a phenomenon, a hygiene hypothesis or the like focusing on changes in enteric bacterial balance has been proposed, but no established theory exists. However, it has been confirmed that such immune diseases share common characteristics such as increases in production of inflammatory cytokines including TNF-α, IL-6, IL-12, IL-17, and the like. Suppression of inflammatory immune cells that proliferate in response to the production and the stimulation of cytokines are expected to be effective for prevention and treatment of these immune diseases. Actually, it has been progressively reported that antibodies targeting the aforementioned cytokines exhibit significant effects in humans.
It is known that a proinflammatory irritant represented by LPS (lipopolysaccharide) is recognized by a toll-like receptor (TLR) on DCs, so as to cause activation and/or maturation of DCs, inducing inflammatory response through the release of various inflammatory cytokines and chemokines. It has been reported that in many immune diseases, abnormal activation of DCs, macrophages, and the like takes place in the natural immune system. Therefore, methods for suppressing such activation of the natural immune system and substances that can suppress the activation of the natural immune system are very effective for prevention and treatment of the above immune diseases.
As agents for inducing DCs exhibiting reduced inflammatory activity, IL-10/TGF-β, rapamycin, vasoactive intestinal peptide (VIP), and the like are currently known. However, these drugs also have many other biological effects, so that the administration thereof to human bodies for prevention and treatment of immune diseases is unrealistic. Hence, a possible method for the use of these agents for prevention and treatment of immune diseases is an ex vivo method that comprises inducing DCs, which have reduced inflammatory activity, from collected blood in vitro, and then returning the DCs to a human body.
An immunosuppressive agent such as FK506 is used to suppress rejection that poses a problem upon tissue or organ transplantation. However, adverse reactions due to nonspecific immunosuppression by existing drugs have been questioned. It has been revealed that regulatory T cells (Treg) in addition to immunosuppressive agents are useful to suppress rejection at the time of transplantation. Treg is known to be induced via secretion of a cytokine from DCs. Therefore, if a method for inducing DCs capable of resulting in production of Treg and a method for directly inducing Treg from naive T cells are developed, such methods could be expected to be useful for suppression of rejection upon transplantation.
In recent studies, retinoic acid, 1,25-dihydroxy vitamin D3, and the like have been rediscovered as substances capable of directly acting on CD4+ T cells so as to induce Treg. These substances are thought to be useful in terms of anti-inflammatory effects, suppression of graft rejection, and the like, similarly to substances that induce DCs exhibiting reduced inflammatory activity.
Patent Literature 1 describes immunopotentiators obtained from fermentation-degraded products which are produced by fermentation of soybean, wheat, rice, or a material containing byproducts thereof using filamentous fungi or an enzyme(s) obtained therefrom. Specifically, patent Literature 1 demonstrates that glucose consumption by macrophages is enhanced by a substance that is obtained by separating an ethanol-insoluble fraction from a fermented product obtained by fermentation of a soybean-derived material or wheat using Aspergillus oryzae or Aspergillus sojae and then further extracting a high-molecular-weight fraction from the above ethanol-insoluble fraction.
Patent Literature 2 describes a macrophage-activating agent obtained by fermentation of a soybean-derived material using lactic acid bacteria.
Patent Literature 3 describes hyaluronidase inhibition, antiallergic activity, and an immunostimulating substance obtained from fermentation-degraded products which are produced by fermentation of soybean, wheat, citrus fruits, fruits, or a material containing a processed product thereof using filamentous fungi, Bacillus subtilis natto, or an enzyme(s) obtained therefrom. Patent Literature 3 describes that a substance obtained by fermentation of a soybean-derived material or wheat using Aspergillus oryzae, separation of an ethanol-insoluble fraction from the fermented product, and then extraction a high-molecular-weight fraction from the ethanol-insoluble fraction has hyaluronidase-inhibiting activity and immunostimulating activity as determined using IgA production from Peyer's patch cells as an indicator.
Patent Literature 4 describes an immunostimulating substance obtained by fermentation of a plant component such as wheat flour using Pantoea agglomerans, which is a Gram-negative bacterium.
Patent Literature 5 describes that a fermented product obtained by fermenting a mixture of a product obtained by means of steam blasting treatment, such as bagasse, and wheat bran using Aspergillus sojae comprises xylobiose- and xylotriose-rich xylo-oligosaccharides and a substance(s) with antioxidation activity.